Abstract Unraveling molecular components and mechanisms that are important to genome stability under mutagen stress is important to basic biology of aging, many cancers and neurological diseases. As an organism that can withstand unusually high levels of ionizing radiation, Deinococcus radiodurans hides a wealth of strategies to manage oxidative stresses that are not all fully understood. The overarching goal of this project is to characterize the biological importance of a newly discovered class of small RNAs that likely mediates regulation of cellular transport during recovery from ionizing radiation (IR)-induced stresses in this organism. We propose the new hypothesis that RNA regulators remain largely functional during radiation in a way that allows them to control multiple transport pathways to initially boost cellular concentration of antioxidants and decrease cellular toxins. Our overall objective is to demonstrate a novel sRNA-mediated regulatory mechanism for cellular transport in response to IR-induced oxidative stresses and to show the impact of this system on proteome protection. We focus on two novel sRNAs (Dsr 8 and Dsr11) given that they are: (i) differentially expressed during IR recovery, (ii) expressed in other radioresistant bacteria, (iii) differentially expressed with increased concentrations of Mn2+ and Fe2+ (two metals that are thought to be highly regulated for proteome protection during stress recovery), and (iv) suspected to bind mRNAs encoding for ABC transporters in vivo. Specifically, we aim to: (1) evaluate the contribution of Dsr8 and Dsr11 sRNAs to radioresistance, and (2) characterize the regulatory effects of Dsr8 and Dsr11 binding to their mRNA targets and the impact of these interactions on radioresistance. We expect this early work to contribute towards identifying key regulation mechanisms for radioresistance in a way that accounts for metabolic exchanges between cells and their environment. By exploring function of a novel class of sRNA regulators that we have uncovered in highly radioresistant bacteria, we will also introduce a model that should allow a more comprehensive view of sRNA regulation in oxidative stress responses. Completion of the proposed work will answer general basic questions about acute oxidative stress management to complement our current studies in epithelial human lung cells. Collectively, these studies will enable a future RO1 proposal on mechanisms of transport regulation (in model human cells) that control ion/metabolite fluxes during recovery from acute oxidative stresses.